We will test the hypothesis that relative podocyte depletion in relation to glomerular area to be served causes glomeruloscierosis (GS). GS is the glomerular scarring process that is associated with progressive loss of renal function leading to ESRD in diabetic, hypertensive, Focal Segmental GS (FSGS) and in hereditary and immune forms of GS. Together these conditions account for about 90 percent of ESRD, major morbidity/mortality and a cost of more than 10 billion dollars per year in the US alone. ESRD is approaching epidemic proportions as the population ages. We know from autopsy reports that GS occurs with increasing frequency above 40 years of age. GS is well documented to be associated with podocyte injury. New data from experimental animals and diabetic man have reinforced the concept that it is the relationship between glomerular area and podocyte count that is critical. Each differentiated podocyte has limited capacity to divide and to cover an increased area of GBM. We hypothesize that if a threshold value for Glomerular Area Per Podocyte (GAPP) is exceeded then GS will result. We will test this hypothesis by developing a mouse transgenic model where degree of podocyte depletion can be determined at will and resu;lting GS measured directly (Aim 1). In Aim 2 we will use rat models to test the hypothesis that podocyte number in relation to glomerular area determines the onset of GS in aging and renal depletion. Aim 3 will evaluate human renal biopsies to establish normal ranges GAPP for age, sex and race and to determine whether diseases associated with GS in man have similar relative podocyte depletion. The identification of podocyte depletion as a major mechanism underlying glomerulosclerosis will be an important step towards development of improved strategies for prevention of progression, new monitoring strategies and new treatments for glomerulosclerosis.